Differential gene regulation by nutrient restriction and hypoxia in cultured human placental extravillous trophoblasts (HTR‐8/SVneo)

Abstract

Both maternal undernutrition and hypoxia impair placental and fetal growth, but the mechanisms are unknown. We cultured trophoblasts in nutrient‐replete media (C; 20% O2), hypoxia (Hx; 1% O2 in nutrient‐replete media), 75% nutrient‐restricted media (NR; 20% O2), or NR‐Hx. Hx or NR alone reduced growth 40–45% and together by 70% (p<0.001). We determined ≥2 fold changes in gene expression by microarray analysis (Agilent Whole Human Genome Microarray 4X44K V2) and GeneSpring V12 compared to C. NR altered expression of the most genes [335 upregulated (Up) and 417 downregulated (Dn)] in contrast to the fewest in Hx (33 Up and 16 Dn genes) and intermediate numbers in NR‐Hx (171 Up and 75 Dn genes). NR, Hx and NR‐Hx only affected 13 genes in common with 4 Up including FBXO32 and ARC involved in protein catabolism and repressing apoptosis, respectively, and 9 Dn including GLI1, OTUD6A and SUCNR1 involved in, respectively, regulation of proliferation through Hedgehog signaling, deubiquitination and mediation of local stress. Two gene pathways were altered (p<0.001; DAVID/KEGG): Up MAPK signaling pathway in NR and Up aminoacyl‐tRNA biosynthesis pathway in NR‐Hx. Although many mechanisms may contribute to impaired placental growth in NR or NR‐Hx, these results suggest only a few possible shared mechanisms through which both NR and Hx impair placental growth. Supported by Cornell University